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PubMed1983

Action of almitrine bismesylate on pulmonary vasculature in the dog: preliminary report.

The effects of almitrine bismesylate on the pulmonary circulation have been investigated in anaesthetized dogs, paralysed and artificially ventilated. An i.v. bolus of almitrine bismesylate (10 micrograms X Kg-1) caused a 35% increase in specific pulmonary vascular resistance under normoxic or hyperoxic conditions but only a 2% increase when pulmonary vessels were constricted by hypoxia (13% inspired O2). With local hypoxia, confined to the retrocardiac lobe, almitrine bismesylate caused lobar vasodilation (specific vascular conductance increased by 10%) while at the same time conductance fell by 38% in the rest of the lung which was hyperoxic. The almitrine-induced vasoconstriction was not abolished by alpha- or beta blockade, indomethacin, vagotomy or bilateral clamping of both common carotids in the neck. With constant ventilation, no rise of arterial PO2 occurred following almitrine bismesylate . In the presence of local hypoxia, the drug by virtue of its inhibition of local hypoxic vasoconstriction caused PaO2 to fall slightly. In conclusion, almitrine bismesylate constricts pulmonary vessels in normoxia and dilates them when they are constricted by hypoxia. The mechanism is unknown but it is likely to be an intra-rather than an extrapulmonary site of action.

Almitrine↗
PubMed1983

Beneficial effects of almitrine bismesylate on pulmonary gas exchange in COPD.

Almitrine bismesylate 100 mg orally was given to eight patients with severe chronic obstructive pulmonary disease (COPD). In five patients, gasometric, haemodynamic and lung mechanics parameters, and almitrine plasma levels were measured at baseline and every hour up to five hours after almitrine bismesylate intake. Maximal almitrine plasma levels were reached after 2 hours (89 +/- 41 ng/ml, mean +/- SEM) and persisted up to the fifth hour (68 +/- 25 ng/ml). Pulmonary vascular resistance increased significantly from baseline 433 +/- 120 dynes.s.cm-5 to 503 +/- 124, p less than 0.05 at the second hour and to 509 +/- 119, p less than 0.05 at the fifth hour. Arterial oxygen saturation increased significantly from baseline 81.7 +/- 4.9% to 84.5 +/- 5.0, p less than 0.05 at the second hour and to 84.5 +/- 4.6, p less than 0.05 at the fifth hour. Venous admixture decreased significantly from baseline 35 +/- 9% to 30 +/- 9, p less than 0.05 at the second hour and to 28 +/- 9, p less than 0.01 at the fifth hour. Pulmonary artery mean pressure, cardiac output and minute ventilation did not change. The continuous distributions of ventilation-perfusion ratios (VA/Q), using the multiple inert gas elimination technique, were determined in six patients, at baseline and two hours after almitrine bismesylate intake. An improvement in VA/Q matching was observed after almitrine with a diversion of an average of 15 per cent of total blood flow from hypoxic units (VA/Q between 0.08 and 0.4) to normoxic units (VA/Q between 0.5 and 1.8).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMedDate not supplied

Action of almitrine on the pulmonary vasculature in ferrets and rats.

The action of almitrine on pulmonary vessels was studied under constant ventilation during normoxia and hypoxia. We used ferrets, in which one lobe of lung was perfused with venous blood at constant flow rate in vivo and isolated lungs perfused with blood at constant flow in both ferrets and normal and chronically hypoxic (three weeks in 10% O2) rats. Almitrine caused constriction of the relaxed vessels of normoxic lung. During hypoxic pulmonary vasoconstriction, when pulmonary artery pressure (Ppa) was raised, almitrine had a dual action; it caused further constriction followed by dilatation over a wide dose range (0.7-118 micrograms X kg-1 in ferrets). Similar effects were seen in normal and chronically hypoxic rats; the latter have narrowed muscularized arterioles like patients with chronic obstructive airways disease. Almitrine caused a larger rise in Ppa in normoxic than hypoxic rat lungs (7.9 instead of 1.7 mmHg; p less than 0.001) and dilatation followed constriction in the latter. Verapamil reduced both the constrictor action of almitrine and hypoxic vasoconstriction and there was a strong correlation between the effect of the two stimuli before and after verapamil (r = 0.9). Attempts to identify a substance which might cause the dilator action of almitrine were unsuccessful.

Almitrine↗
PubMed1990

Pattern of breathing and laryngeal patency following almitrine bismesylate in anesthetized cats.

The effects of almitrine bismesylate on the pattern of breathing and laryngeal caliber were investigated in anesthetized, spontaneously breathing cats. Breathing occurred via a tracheostomy, while the laryngeal resistance to airflow was measured with the larynx isolated in situ. Almitrine bismesylate in a dose of 0.5 mg/kg of body weight was injected intravenously three times: in the intact animals, following bilateral vagotomy (sparing the right recurrent laryngeal nerve), and after a sensory denervation of the larynx. In each condition, almitrine stimulated ventilation by significantly increasing inspiratory airflow, by increasing the respiratory rate in the 10th and the 20th minutes following injection, and by reducing laryngeal resistance to airflow in both the inspiratory and expiratory phases. The stimulatory effects of almitrine were most apparent in the intact animals. Following vagotomy, these significant changes in the pattern of breathing as well as the enlarged laryngeal caliber persisted. However, these latter effects were short-lived and were followed by narrowing of the laryngeal lumen. Laryngeal afferents were not essential for the response to almitrine.

Airway Resistance↗
PubMed1992

Normotensive normoxic men undergoing water diuresis fail to respond to stimulation of their peripheral arterial chemoreceptors by almitrine with an increase in plasma concentrations of atrial natriuretic factor.

The purpose of this study was to investigate the possible participation of atrial natriuretic factor (ANF) in the natriuretic and diuretic response occurring after stimulation of the peripheral arterial chemoreceptors by almitrine bismesylate in normoxic humans. The experiments were performed in 14 healthy male volunteers undergoing water diuresis. Each subject participated in two experiments. In one of them they ingested 100-mg almitrine at 12 p.m. The other study served as a control. Surprisingly, our subjects responded to almitrine with an elevation of urine flow only, whereas sodium excretion remained almost unchanged over the whole period of the experiments. As regards ANF plasma concentrations, no statistically significant differences between the control and the almitrine group could be observed. Moreover, no direct connection between ANF plasma concentrations and renal volume excretion was detectable. We conclude that a specific stimulation of peripheral arterial chemoreceptors by almitrine in humans undergoing water diuresis did not seem to raise ANF plasma concentrations as is the case at high altitude. Therefore we would suggest that there exists no specific reflex influence of these receptors on ANF release.

Administration, Oral↗
PubMed1997

Differential effects of ventilatory stimulation by sex hormones and almitrine on hypoxic erythrocytosis.

In the absence of pulmonary disease, hypoventilation is considered to be the primary cause of Chronic Mountain Sickness, and there is some reason to believe that chronic administration of respiratory analeptics could be useful for treatment of this disease. The present study was intended to define comparatively the influence of two potent ventilatory stimulants, namely a combination of progesterone and estrogen and the pharmacological agent almitrine, on catecholaminergic structures implicated in the chemoreflex pathway and on hypoxia-induced polycythemia. Three groups of young male rats born and living at high altitude (3 600 m) were examined: untreated animals (n = 25), rats given ovarian steroids (progesterone plus 17beta-estradiol, n = 25) or almitrine (n = 25) for 6 weeks until sacrifice. Ovarian steroids or almitrine had pronounced neurochemical effects on the afferent chemoreflex circuitry. Both treatments inhibited norepinephrine (NE) and dopamine (DA) turnover in the carotid body, but central processing of chemosensory inputs differed between the two respiratory drugs. Ovarian steroids inhibited noradrenergic activity in the projection area of the chemosensory nerve fibers within the caudal portion (A2C) of the nucleus tractus solitarius (NTS). In contrast, almitrine stimulated neurochemical activity of other brainstem noradrenergic cell groups involved in cardiorespiratory control, i.e. , the rostral portion (A2R) of the NTS, the nucleus reticularis lateralis (A1), the nucleus olivaris superior (A5) and the locus ceruleus (A6). Although both treatments increased chemoreflex drive and ventilation, only sex hormones decreased erythropoietin (EPO) levels and the degree of polycythemia. These results suggest that stimulation of ventilation through activation of peripheral arterial chemoreceptors activation alone is not sufficient for reducing EPO levels and polycythemia. The better efficiency of female sex hormone treatment as compared to almitrine could be related either to the central effects of progesterone and estrogen and/or to the impact of these hormones on erythropoiesis at the kidney/bone marrow level.

Almitrine↗
PubMed1988

The effect of almitrine bismesylate on the steady-state responses of arterial chemoreceptors to CO2 and O2 in the cat.

The interaction between almitrine bismesylate, a pharmacological stimulant of peripheral chemoreceptors, and varying levels of oxygen (PO2 50-600 Torr) and carbon dioxide (PCO2 10-65 Torr) on steady state carotid chemoreceptor discharge was investigated in pentobarbitone-anaesthetised cats. Almitrine was given as constant intravenous (50 micrograms/kg per min for 4 min) and intracarotid infusions (4-16 micrograms/kg per min) at different levels of alveolar PO2 and PCO2. Almitrine always excited discharge. The intracarotid infusions at the lower infusion rate (4-8 micrograms/kg per min) and the i.v. infusions increased the slope of the isoxic response to CO2. This effect could be reversed by raising PO2 to high levels. Higher infusion rates of almitrine (16 micrograms/kg per min) displaced the CO2 response curve upwards but did not increase its slope above that obtained in control conditions at end-tidal PO2 of 50 Torr. However, as these higher infusion rates caused levels of discharge greater than those achieved during control conditions, their effects on control CO2 sensitivity could not be ascertained. Our results suggest that almitrine excites carotid body chemoreceptors by a mechanism similar to that of hypoxia and not like that of carbon dioxide.

Almitrine↗
PubMed1983

The pulmonary haemodynamic effects of almitrine infusion in men with chronic hypercapnia.

1. Almitrine, an agonist of peripheral chemoreceptors, has been shown to be effective in lowering PaCO2 in patients with chronic obstructive lung disease. The aim of this investigation was to evaluate the pulmonary haemodynamic response to almitrine in clinically stable patients with chronic airflow obstruction and chronic hypercapnia (PaCO2 7.1 +/- 0.5 kPa, mean +/- SD). 2. Seven men, aged from 55 to 64 years, had the following values for pulmonary function (means +/- SD): FEV1.0 0.67 +/- 0.16 litre; VC 2.12 +/- 0.52 litres; FEV1.0/VC 33 +/- 8%. They had haemodynamic monitoring during 1 h of almitrine (1 mg/kg intravenously) and solvent (placebo) in a random fashion while receiving 28% oxygen. Before infusion, six patients had evidence of pulmonary hypertension and the mean pulmonary artery pressure (PAP) for all seven patients was 4.3 +/- 1.6 kPa (mean +/- SD); the pulmonary vascular resistance (PVR) was 0.61 +/- 0.22 kPa 1(-1)s (mean +/- SD). 3. There were no significant changes from baseline values during placebo. During almitrine, however, the PAP and right ventricular stroke work (mean +/- SD) increased significantly at 30 min (6.0 +/- 2.1 kPa, P less than 0.001, 0.38 +/- 0.12 J, P less than 0.05, respectively) with maximum increase of PVR at 45 min (1.01 +/- 0.34 kPa 1(-1)s, P less than 0.001, mean +/- SD). The lowest PaCO2 (mean +/- SD) was observed at the end of the infusion (5.7 +/- 0.5 kPa, P less than 0.001). 4. These results confirm the benefit of almitrine in lowering PaCO2 in patients with chronic airflow obstruction who have chronic hypercapnia but also demonstrate significant pulmonary vasoconstriction.

Almitrine↗
PubMed1984

The effects of oral almitrine on pattern of breathing and gas exchange in patients with chronic obstructive pulmonary disease.

Almitrine at a low dose of 100 mg orally significantly raises PaO2 and lowers PaCO2 in patients with chronic obstructive pulmonary disease, compared with placebo, when they were breathing air or 28% oxygen. The estimated ideal alveolar-arterial PO2 difference was less after almitrine compared with placebo, when patients were breathing either air or 28% oxygen. After almitrine overall ventilation breathing air increased by 10% but this did not reach statistical significance. During 28% oxygen breathing almitrine hardly altered overall ventilation but the inspiratory duty cycle (Ti/Ttot.) decreased and mean inspiratory flow rate (VT/Ti) increased compared with placebo. These changes were significant on a paired t-test (P less than 0.05). Changes in both volume and pattern of breathing may explain the improved gas exchange in the lung after almitrine.

Administration, Oral↗
PubMed1989

Effect of almitrine on hypoxic ventilatory drive measured by transient and progressive isocapnic hypoxia in normal men.

1. In a double-blind placebo-controlled study, we have investigated the effect of the peripheral chemoreceptor stimulant drug almitrine bismesylate on hypoxic ventilatory drive (expressed as the slope of the minute ventilation/arterial oxygen saturation relationship in litres min-1+-1) as measured by both progressive isocapnic hypoxia at rest and transient hypoxia (three breaths of 100% N2) during moderate exercise, in seven normal men, to determine if the ventilatory response to the transient hypoxic stimulus is a more specific measure of peripheral chemoreceptor sensitivity to hypoxia. 2. Hypoxic ventilatory drive measured using progressive isocapnic hypoxia ranged from -0.13 to -2.65 litres min-1%-1 after placebo and from -0.20 to -6.48 litres min-1%-1 after almitrine. The response was greater after almitrine in six of the seven subjects, and the difference was significant for the whole group (P less than 0.05). 3. Hypoxic ventilatory drive measured using transient hypoxia ranged from -0.19 to -1.59 litres min-1%-1 after placebo and from -0.09 to -1.62 litres min-1%-1 after almitrine. The response was not consistently greater after almitrine, and the difference was not significant for the group. 4. Difficulties in accurately quantifying a brief rise in minute ventilation after transient hypoxia, particularly in subjects with a low hypoxic ventilatory drive, may have masked small changes in the slope of the minute ventilation/arterial oxygen saturation relationship with this method.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

[Effect of almitrine and oxygen on arterial blood gases in chronic respiratory insufficiency].

In patients with respiratory failure, almitrine causes an increase in arterial O2 partial pressure (paO2) by stimulating peripheral chemoreceptors. Since such patients often require long-term O2 therapy inhibiting peripheral chemoreceptor activity, the effect on arterial blood gases by almitrine (100 mg orally) and increasing amounts of nasally supplied O2 was studied. In ten patients with severe chronic airways obstruction and pulmonary emphysema, almitrine produced a mean increase of paO2 by 5.2 mm Hg both while breathing normal air and during nasal administration of O2 (0.5-2.0 l/min), whereas paCO2 levels remained constant. In 4 patients with pulmonary fibrosis almitrine did not change the paO2. These results show that patients with chronic airways obstruction and pulmonary emphysema respond to a single dose of 100 mg almitrine by an increase of paO2 equivalent to that achieved by administering 1.0 l/min of O2 via the nose.

Almitrine↗
PubMed2002

The effects of intravenous almitrine on oxygenation and hemodynamics during one-lung ventilation.

UNLABELLED: One-lung ventilation (OLV) induces an increase in pulmonary shunt sometimes associated with a decrease in PaO2 despite ventilation with 100% oxygen. PaO2 improvement has been reported in one-lung ventilated animals receiving IV almitrine, a pulmonary vasoconstrictor. We evaluated the ability of almitrine to prevent a decrease in PaO2 during OLV. Patients without pulmonary hypertension undergoing OLV for lung surgery were randomly assigned to receive either placebo (Group P, n = 8) or almitrine infusion at a rate of 8 microg x kg(-1) x min(-1) (Group A, n = 8) from the start of OLV. Gasometric and hemodynamic values were recorded with the patient in the lateral decubitus position during two-lung ventilation and at 10-min intervals during OLV over a 30-min period (OLV-10, OLV-20, OLV-30). Compared with the values found during two-lung ventilation (434 +/- 22 mm Hg in Group P and 426 +/- 23 mm Hg in Group A), PaO2 decreased at OLV-10 (305 +/- 46 mm Hg), OLV-20 (203 +/- 20 mm Hg), and OLV-30 (178 +/- 18 mm Hg) in Group P (P < 0.05) and at OLV-20 (354 +/- 25 mm Hg) and OLV-30 (325 +/- 17 mm Hg) in Group A (P < 0.05). PaO2 values differed between the groups at OLV-20 and OLV-30 (P < 0.05). Pulmonary artery pressure and cardiac output did not change. In conclusion, 8 microg x kg(-1) x min(-1) IV almitrine prevents and limits the OLV-induced decrease in PaO2 without causing any hemodynamic modification. IMPLICATIONS: Eight microg x kg(-1) x min(-1) IV almitrine limits one-lung ventilation-induced decrease in PaO2 without causing any hemodynamic modification in patients without pulmonary hypertension.

Almitrine↗
PubMed1987

High-dose almitrine bismesylate inhibits hypoxic pulmonary vasoconstriction in closed-chest dogs.

The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in seven closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was ventilated with either 100% O2 ("hyperoxia") or with an hypoxic gas mixture ("hypoxia": end-tidal PO2 = 50.1 +/- 0.1 mmHg). Cardiac output (CO) was altered from a "normal" value of 3.10 +/- 0.18 l . min-1 to a "high" value of 3.92 +/- 0.16 l . min-1 by opening arteriovenous fistulae which allowed measurements of two points along a pressure-flow line. These four phases of left lung hypoxia or hyperoxia with normal and high cardiac output were repeated in the presence and absence of almitrine. Almitrine bismesylate was administered as a constant infusion of 14.3 micrograms . kg-1 . min-1 for a mean plasma concentration of 219.5 +/- 26.4 ng . ml-1. Relative blood flow to each lung was measured with a differential CO2 excretion (VCO2) method corrected for the Haldane effect. With both lungs hyperoxic, the percent left lung blood flow (%QL-VCO2) was 44 +/- 1%. When the left lung was exposed to hypoxia, the %QL-VCO2 decreased significantly to 22 +/- 1%. However, with the administration of almitrine, the %QL-VCO2 during left lung hypoxia increased significantly to 36 +/- 2%. The arterial oxygen tension decreased significantly between hyperoxia (PaO2 = 633 +/- 6 mmHg) and hypoxia (271 +/- 31 mmHg). With the addition of almitrine, there was no change during hyperoxia; however, during hypoxia, the PaO2 decreased significantly to 124 +/- 15 mmHg. Cardiac output did not influence these findings. The pulmonary vascular conductance (G) is the slope of the pressure-flow line.(ABSTRACT TRUNCATED AT 250 WORDS)

Almitrine↗
PubMed1993

Nifedipine inhibits the effects of almitrine in patients suffering from pulmonary artery hypertension secondary to chronic obstructive pulmonary disease.

It has been suggested that almitrine improves the local ventilation/perfusion ratio by enhancing hypoxic pulmonary vasoconstriction (HVC), leading to an increase in pulmonary vascular resistance (PVR) and PaO2. The goal of the present study was to determine if pulmonary vasodilation induced by nifedipine inhibits the enhancement of HVC (and consequently of PaO2), in patients suffering from chronic obstructive pulmonary disease (COPD). Two groups of 10 patients were compared in a controlled, double-blind study. Hemodynamics and blood gases were measured during continuous infusion of placebo or almitrine (8 micrograms/kg/min). Two hours after the onset of the infusion, a single dose of nifedipine (10 mg) was given sublingually. Almitrine infusion was followed by an increase in PaO2 (20%) and PVR (48%). In the almitrine group, after nifedipine, the PVR decreased 33% and PaO2 dropped to baseline while in the placebo group the PVR decreased 22% and PaO2 fell to 11% below baseline. In COPD patients, nifedipine inhibits almitrine-induced pulmonary vasoconstriction.

Almitrine↗
PubMed1994

Decrease in cytosolic ATP/ADP ratio and activation of pyruvate kinase after in vitro addition of almitrine in hepatocytes isolated from fasted rats.

Previously, we have shown in experiments with isolated mitochondria that almitrine, a drug used for patients with chronic lung disease, affects the H+/ATP stoichiometry of the F0F1-ATPase [Rigoulet, M., Fraisse, L., Ouhabi, R., Guérin, B., Fontaine, E. & Leverve, X. M. (1990) Biochim. Biophys. Acta 1018, 91-97]. In the present study, we have investigated the effect of almitrine on gluconeogenesis and oxygen consumption in isolated hepatocytes. Almitrine decreased both the cytosolic and mitochondrial ATP/ADP ratios but had no effect on oxygen consumption in cells incubated with and without octanoate. This must have been due to a double effect. On the one hand, a decrease in the ATP/ADP ratio decreases ATP utilization; on the other hand, in the presence of almitrine more oxygen is required to synthesize ATP. Almitrine did affect gluconeogenesis from various substrates (lactate + pyruvate, glycerone or fructose), but had no effect on glycerol or glutamine metabolism. The effect on gluconeogenesis from glycerone was due to an increase in glycolytic flux. The rate of lactate + pyruvate production increased whereas there was no effect on glycerone utilization. This effect was caused by an activation of pyruvate kinase. Our data indicate that this enzyme is an extremely sensitive sensor of the cytosolic ATP/ADP ratio. Hence, under our experimental conditions, the cytosolic ATP/ADP ratio decrease affects only the balance between glucose and lactate + pyruvate productions, and not the phosphorylation of glycerone, the first and controlling step of this pathway.

Adenosine Diphosphate↗
PubMed1996

Cardiorespiratory and renal responses to arterial chemoreceptor stimulation by hypoxia or almitrine in men.

1. The cardiorespiratory and renal responses to 3 h of normobaric whole-body hypoxic hypoxia (FiO2 = 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls. 2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole-body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration-fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant. 3. Renal fractional lithium excretion decreased significantly in response to whole-body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes. 4. The data indicate that, in humans, both almitrine and whole-body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics. 5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well-tolerated, whole-body hypoxic hypoxia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown mechanisms.

Adult↗
PubMed1992

An analysis of the action of an analogue of almitrine bismesylate in the rat model of hypoxic lung disease.

Chronically hypoxic (CH) and normoxic control rats were used to assess the action of S9581, a water-soluble analogue of almitrine bismesylate. S9581 increased ventilation (Ve) by 34% in control and 20% in CH rats. During acute hypoxia Ve was raised and S9581 caused a further increase of 20% in both groups. Low doses of S9581 and almitrine enhanced the hypoxic ventilatory response in CH rats while high doses depressed it in both groups. Effects of S9581 on the pulmonary circulation were assessed in the isolated perfused lung of rats. As with almitrine a complex relationship of dose-dependent vasoconstriction and dilatation was revealed. In low doses, S9581 enhanced the hypoxic pulmonary vasoconstrictor response to 2% O2 whilst this was attenuated by high doses in both control and CH rats. S9581 seemed to act like almitrine bismesylate on both the ventilation (peripheral chemoreceptor) and the pulmonary circulation. For studying almitrine-like activity the water solubility of S9581 provides considerable advantages for the researcher.

Almitrine↗
PubMed1989

Peripheral nerve function in patients with chronic bronchitis receiving almitrine or placebo.

A double blind prospective study of the effect of almitrine bismesylate and placebo on peripheral-nerve function was carried out in 12 patients with chronic bronchitis and arterial hypoxaemia (mean (SD) FEV1% predicted 38 (16), arterial oxygen tension (PaO2) 7.56 (0.76) kPa). Of the seven patients who took placebo, none developed symptoms or signs of peripheral neuropathy. One patient who had abnormal lower limb sensory nerve conduction initially showed improvement of sensory conduction but deterioration in motor conduction during the 12 month study period. Two further patients developed some slowing of motor conduction velocities in their right lateral popliteal nerve. Five patients received almitrine and all showed an improvement in PaO2 (mean from 7.0 to 7.9 kPa). None had symptoms or signs of peripheral neuropathy on entry to the study; one patient had evidence of impaired nerve conduction on electrophysiological testing. Three patients developed symptoms and signs of peripheral neuropathy during the 12 months of the study and a fourth developed peripheral neuropathy at 18 months, having continued to receive almitrine. Studies of nerve physiology showed abnormalities in the lower limbs of all four patients. Recovery was poor, possibly because of the long half life of almitrine. The studies suggest that almitrine may precipitate peripheral neuropathy in patients with chronic obstructive pulmonary disease. Patients should be warned of this potential complication so that the drug can be stopped as soon as symptoms develop.

Aged↗